Intermediate Filaments-Desminopathy

Where do the mutations occur in desminopathy?

Desmin and AlphaB-Crystallin

Where is the DES gene located?

Chromosome 2q35

q=long arm

Where is DES expresed?

Striated muscles

Skeletal muscle

Cardiac muscle

Where is the CRYAB gene located?

Chromosome 11q22.3

What does CRYAB gene encode?

AlphaB-crystallin

(small heat shock protein)

Is a Chaperone protein

What causes desminopathy?

Autosomal dominant

Autosomal recessive

Sporadic

When does autosomal dominant desminopathy occur?

When a single copy of the mutated gene is sufficient to cause disorder

When does autosomal recessive desminopathy occur?

Two copies of the mutated gene are needed

When do sporadic cases of desminopathy occur?

Due to de novo mutations

Types of DES gene mutations

-Missense

-Nonsense

-Frameshift

-Splice site

What is the most common DES mutation?

Missense

Result in a single amino acid substitution

What is the impact of mutations on Desmin assembly?

DES gene mutations disrupt the normal assembly of desmin filaments

Impairs proper folding of proteins

Filamentous network disruption

Disorganisation and loss of filamentous network within muscle cells

Disruption weakens structural integrity of muscle fibres

Affects connections between adjacent muscle fibres

Cytoskeletal protein aggregates

Accumulate within muscle cells

Aggregates are composed of aggregated desmin/alhpab-crystallin and myotilin

What diagnostic imaging can look for desminopathy and what does it show?

MRI:

-Muscle atrophy

-Fatty infiltration

-Oedema

Why are histopathology tests crucial for testing for desminopathy?

-Presence of abnormal desmin aggregates

-Cytoskeletal protein accumulation

-Myofiber degeneration and regeneration

What tests are done to confirm desminopathy?

-Clinical evaluation

-Imaging studies

-Muscle biopsies

-Genetic testing

Why do so many tests need to be performed to confirm desminopathy?

Similar clinical features to other neuromuscular disorders eg:

-Limb-girdle muscular dystrophy

-Myofibrillar myopathy

Current treatment strategies for desminopathy

-No cure

-Treatment focuses on managing symptoms and improving quality of life

-Combination of pharmacological and non-pharmacological approaches

Medication used to treat cardiac symptom of desminopathy

Beta-blockers or anti-arrhythmics

Control conduction blocks and arrhythmias

ICD (Implantable Cardiac Defibrillator)

What medication can be used to treat heart failure symptoms in desminopathy?

Diuretics

ACE inhibitors

Angiotensin receptor blockers (ARBs)

manage fluid retention and improve cardiac function

Therapeutic interventions for desminopathy

Address respiratory muscle weakness

Multidisciplinary care

Physical therapy and rehabilitation

What is the impact of the quality of life for a patient with desminopathy?

-Hard to do tasks individually

-Immobility

-Require assistance

-Fatigue

-Muscle weakness

What is intermediate filament?

Structural proteins

provide mechanical strength and support for cells

What does the mutated DES gene damage first?

Causes disorganisation of the Z disc

What is the impact of advanced desminopathy on a molecular level?

Form insoluble deposits and cause myopathy by disrupting myofibrils

Breaks connections between cells

What age does desminopathy occur?

Normally between 30-60 year old

Symptoms of desminopathy

-Muscle weakness:mainly proximal muscles but sometimes distal muscles

-Cardiac problems

-Respiratory problems

-GI problems

What is the purpose of physiotherapy for a patient with desminopathy?

Improve muscle strength, flexibility and overall mobility

Emerging therapies to treat desminopathy

Gene therapy

RNA based therapy

Biologics (small molecules)